Mutational profiling of kinases in glioblastoma

BMC Cancer

Fonnet E Bleeker⁶  Simona Lamba⁷  Carlo Zanon⁵  Remco J Molenaar¹⁰  Theo JM Hulsebos²  Dirk Troost¹  Angela A van Tilborg⁹  W Peter Vandertop⁴  Sieger Leenstra³  Cornelis JF van Noorden¹⁰  Alberto Bardelli⁸ 

[1] Department of Neuropathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

[2] Department of Neurogenetics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

[3] Department of Neurosurgery, Erasmus Medical Center, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands

[4] Neurosurgical Center Amsterdam, Location Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HZ, Amsterdam, The Netherlands

[5] Neuroblastoma Laboratory, Pediatric Research Institute, Fondazione Città della Speranza, Corso Stati Uniti 4, 35127 Padua, Italy

[6] Department of Clinical Genetics, Academic Medical Center and University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

[7] Department of Oncology, University of Torino, SP 142, Km 3.95, Candiolo, Torino, 10060, Italy; Candiolo Cancer Institute – FPO, IRCCS, Candiolo, Torino, Italy

[8] FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy

[9] Department of Pathology, UMC St. Radboud, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands

[10] Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

关键词: PI3K-AKT;    Mutation;    Molecular;    Gene;    Kinase;    Glioblastoma;   

Others  :  1121022
DOI  :  10.1186/1471-2407-14-718

 received in 2014-04-14, accepted in 2014-09-17,  发布年份 2014

【 摘 要 】

Background

Glioblastoma is a highly malignant brain tumor for which no cure is available. To identify new therapeutic targets, we performed a mutation analysis of kinase genes in glioblastoma.

Methods

Database mining and a literature search identified 76 kinases that have been found to be mutated at least twice in multiple cancer types before. Among those we selected 34 kinase genes for mutation analysis. We also included IDH1, IDH2, PTEN, TP53 and NRAS, genes that are known to be mutated at considerable frequencies in glioblastoma. In total, 174 exons of 39 genes in 113 glioblastoma samples from 109 patients and 16 high-grade glioma (HGG) cell lines were sequenced.

Results

Our mutation analysis led to the identification of 148 non-synonymous somatic mutations, of which 25 have not been reported before in glioblastoma. Somatic mutations were found in TP53, PTEN, IDH1, PIK3CA, EGFR, BRAF, EPHA3, NRAS, TGFBR2, FLT3 and RPS6KC1. Mapping the mutated genes into known signaling pathways revealed that the large majority of them plays a central role in the PI3K-AKT pathway.

Conclusions

The knowledge that at least 50% of glioblastoma tumors display mutational activation of the PI3K-AKT pathway should offer new opportunities for the rational development of therapeutic approaches for glioblastomas. However, due to the development of resistance mechanisms, kinase inhibition studies targeting the PI3K-AKT pathway for relapsing glioblastoma have mostly failed thus far. Other therapies should be investigated, targeting early events in gliomagenesis that involve both kinases and non-kinases.

【 授权许可】

   
2014 Bleeker et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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